This five-year study will compare for the first time nortriptyline (NT) concentration-effect relationships in elderly major depressives with and without cognitive dysfunction. Our pilot studies in nondemented patients indicated orderly relationships between plasma concentrations of the active metabolite 10-hydroxy-nortriptyline (10-OH-NT) as well as NT, and both antidepressant response and toxicity; also, brain ventricle enlargement was associated with different concentration-effect relationship in the affective dimension. In an initial sample studied using a fixed-dose design, relationships between plasma drug concentrations and affective change, changes in cognitive performance, and cardiovascular status and subjective side effects have now been noted. Cognitive dysfunction was associated with differences in concentration-effect relationships in the affective and cognitive dimensions during treatment. Patients aged equal to or greater than 65 years with major depression will be monitored during six weeks of NT at a fixed final dose. Cognitive function will be reassessed after affective symptoms have remitted. Serial free and total plasma NT and 10-OH-NT concentrations, and binding proteins, will be determined. Brain magnetic resonance images will be obtained. Hypotheses to be tested are: 1) affective improvement has a positive linear association and weaker curvilinear association with plasma NT, and is associated with lower 10-OH-NT; 2) improvement in cognitive performance is associated with higher Z-10-OH-NT but lower NT; 3) high plasma E-1O-OH-NT is associated with emergent orthostatic blood pressure changes; also, subjective side effects, intracardiac conduction prolongation, and changes in ventricular ectopy are better ordered by consideration of 10-OH-NT in addition to NT. Free drug concentrations are better correlated with all response measures than total drug measures. Further, 4) patients with cognitive dysfunction/dementia and 5) patients with ventricle dilatation on MRI each differ in concentration-effect relationships in the affective and cognitive dimensions from patients without these features. Cognitively impaired elderly depressives are a prevalent subgroup virtually unstudied in regard to antidepressant concentration-effect relationships. The study will provide data critically needed for clinical practice and for use of NT as a research tool.